Since its discovery in 1979, p53 has been the most intensively studied molecule in biomedical research and described as the most important tumor suppressor in human cancer. The more we study p53 the less we know about it as depicted by the cover of this issue. To celebrate the 40th anniversary of p53 discovery, to cheer researchers who have dedicated their entire careers to study p53, and to help readers better understand p53 and its history, this special issue of Journal of Molecular Cell Biology (JMCB) has fortunately collected remarkably interesting and historical papers from a number of hard core p53 researchers in the field of cancer, many of whom are pioneering and world-class scientists.